Comparing autonomic and cardiovascular responses in
African and Caucasian men:
The SABPA Study
Aletta Sophia Uys
20030223
Thesis submitted in fulfilment of the requirements for the degree Philosophiae Doctor in Physiology at the Hypertension in Africa Research Team (HART) of the North-West
University, Potchefstroom Campus
Promoter: Prof L Malan
Co-promoter: Prof JM van Rooyen
Assistant promoters: Prof HS Steyn Prof Dr T Ziemssen Dr M Reimann
i
ACKNOWLEDGEMENTS
Firstly, I would like to acknowledge my Heavenly Father for His infinite grace, the strength He has given me as well as all the blessings I have received;
I owe my deepest gratitude to the following people who have all made an invaluable contribution in the process of writing this thesis:
Prof Leoné Malan, my promoter, for her patience, guidance, support and love not only in the writing
of this thesis, but throughout the development of my research career.
Prof Johannes M van Rooyen, my co-promoter, for his advice and valuable input in the writing of
this thesis.
Prof Faans (HS) Steyn, my assistant promoter, who helped me overcome the statistical obstacles. Dr Manja Reimann, my assistant promoter, for her insight and expert input.
Prof Dr Tjalf Ziemssen, my assistant promoter, for his expertise and scientific input. Ms Cecilia van der Walt, for language editing (see attached confirmation).
My parents, words cannot describe my gratitude for their endless love, support, guidance and
encouragement.
My husband, whose love and encouragement has given me the strength to complete this thesis. My sister, brother-in-law and grandmother, for all their love and support.
My late grandfather, for his strength and determination. It will always be an inspiration to me never to
give up.
The financial assistance of the National Research Foundation (DAAD-NRF) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at, are those of the author and are not necessarily to be attributed to the DAAD-NRF.
ii
TABLE OF CONTENTS
ACKNOWLEDGEMENTS ... i
TABLE OF CONTENTS ... ii
SUMMARY ... vi
OPSOMMING ... x
PREFACE ... xiv
LIST OF ABBREVIATIONS ... xix
CHAPTER 1: LITERATURE STUDY, AIM AND HYPOTHESES
1. INTRODUCTION ... 2
2. AN OVERVIEW OF AUTONOMIC CONTROL OF CARDIOVASCULAR
FUNCTION ... 3
2.1. Central nervous system control ... 3
2.2. The sympathetic nervous system and its role in cardiovascular control... 4
2.2.1. Adrenergic control of the heart ... 6
2.2.2. Adrenergic control of the vasculature ... 7
2.2.3. Catecholamine elimination ... 8
2.2.4. Adrenergic stress response patterns ... 8
2.3. The parasympathetic nervous system and its role in cardiovascular control ... 9
2.3.1. Cholinergic control of the heart ... 10
iii
2.3.3. Elimination of acetylcholine... 11
2.4. Regulating adrenergic and cholinergic control of cardiovascular function - The baroreceptor reflex ... 11
2.5. Relationship between autonomic cardiovascular control and the endothelium ... 12
3. AUTONOMIC AND CARDIOVASCULAR DYSFUNCTION ... 13
3.1. The neurogenic component of hypertension ... 13
3.1.1. Reduced baroreceptor sensitivity ... 14
3.1.2. Nocturnal hypertension ... 15
3.2. Target organ damage development ... 16
3.2.1. Atherosclerosis... 16
3.2.2. Left ventricular hypertrophy ... 17
4. AUTONOMIC AND CARDIOVASCULAR DYSFUNCTION CONCERNING
AFRICANS ... 18
5. AIMS ... 20
5.1. Overarching aim ... 20
5.2. Detailed aims ... 20
5.2.1. Chapter 2 – Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: The SABPA study ... 20
5.2.2. Chapter 3 – Nocturnal blood pressure, 3-methoxy-4-hydroxy-phenylglycol and carotid intima-media thickness: The SABPA study ... 21
5.2.3. Chapter 4 – Nitric oxide, cardiovascular function and structural vascular disease in men: The SABPA study... 21
6. HYPOTHESES ... 21
6.1. Overarching hypotheses ... 21
iv
6.2.1. Chapter 2 – Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: The SABPA study ... 22
6.2.2. Chapter 3 – Nocturnal blood pressure, 3-methoxy-4-hydroxy-phenylglycol and carotid intima-media thickness: The SABPA study ... 22
6.2.3. Chapter 4 – Nitric oxide, cardiovascular function and structural vascular disease in men: The SABPA study... 23
7. REFERENCES ... 24
CHAPTER
2:
BARORECEPTOR
SENSIVITITY,
CARDIOVASCULAR
RESPONSES AND ECG LEFT VENTRICULAR HYPERTROPHY IN MEN: THE
SABPA STUDY... 34
CHAPTER 3: NOCTURNAL BLOOD PRESSURE,
3-METHOXY-4-HYDROXY-PHENYLGLYCOL AND CAROTID INTIMA-MEDIA THICKNESS: THE SABPA
STUDY ... 60
CHAPTER
4:
NITRIC
OXIDE,
CARDIOVASCULAR
FUNCTION
AND
STRUCTURAL VASCULAR DISEASE IN MEN: THE SABPA STUDY ... 88
CHAPTER 5: GENERAL FINDINGS AND CONCLUSIONS
1. Introduction ... 116
2. Summary of main findings ... 116
2.1. Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: The SABPA study (Chapter 2) ... 116
2.2. Nocturnal blood pressure, 3-methoxy-4-hydroxy-phenylglycol and carotid intima-media thickness: the SABPA study (Chapter 3)... 117
2.3. Nitric oxide, cardiovascular function and structural vascular disease in men: the SABPA study (Chapter 4) ... 118
3. Comparison of findings with literature ... 119
v
4. Chance and confounding ... 121
5. Discussion of main findings ... 122
6. Conclusions ... 124
7. Recommendations ... 125
vi
Title: Comparing autonomic and cardiovascular responses in African and Caucasian men: The SABPA Study.
SUMMARY
Motivation
Hypertension is a pertinent health problem for urban black African men (hereafter referred to as African). Sympathetic hyperactivity and a dominant α-adrenergic response pattern have both been implicated as contributing factors to their poor cardiovascular health. In addition to the deleterious effect of neurogenic hypertension on target organs, sympathetic hyperactivity may promote the accelerated progression of left ventricular hypertrophy and structural vascular disease.
Aim
The overarching aim of this study is to scrutinize autonomic control of the cardiovascular system in a cohort of urban African and Caucasian men during a mental challenge. Associations were investigated between potential sympatho-vagal imbalance, blood pressure and target organ damage markers to determine cardiovascular risk in ethnic male groups.
Methodology
The SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study involved the participation of 200 male teachers (99 African and 101 Caucasian) in the Kenneth Kaunda Education District of the North-West Province, South Africa. Of the participant group, HIV-infected (13 African) and clinically confirmed diabetics (1 Caucasian and 6 African men) were excluded from further analyses. Stratification was based on ethnicity and further as indicated through statistical interaction effects. Cardiovascular and autonomic responses were assessed during rest and on stressor exposure (cold pressor test
vii
and Stroop colour-word conflict test). Autonomic measures included baroreceptor sensitivity (BRS), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and nitric oxide metabolite (NOx) levels. Cardiovascular variables consisted of blood pressure, cardiac output, stroke volume, total peripheral resistance, heart rate, arterial compliance and ST-segment from the 12-lead electrocardiogram. Markers of target organ damage included the Cornell product (indication of left ventricular hypertrophy) and carotid intima-media thickness as indication of structural vascular disease. Means and proportions were compared by means of standard t-test and Chi-square test, respectively. Significant differences of mean cardiovascular and autonomic measures between ethnic male groups were also determined through analysis of covariance. Uni- and multivariate regression analyses were employed to demonstrate associations between target organ damage, cardiovascular and autonomic markers.
Results and conclusion of each manuscript
To assess autonomic nervous system and cardiovascular function as well as target organ damage, we clearly focussed on responses where our participants were challenged. Markers of autonomic responses assessed were baroreceptor sensitivity, 3-methoxy-4-hydroxy-phenylglycol and nitric oxide metabolites.
The first manuscript (Chapter 2) focused on left ventricular hypertrophy as marker of target organ damage, blood pressure and baroreceptor sensitivity as marker of autonomic function. The objective was to determine whether BRS was significantly lower in African men than in the Caucasian men. Furthermore, the possible association between attenuation of BRS and increased levels of ambulatory blood pressure as well as left ventricular hypertrophy was investigated in these population groups. Results revealed that the African men had significantly lower BRS stress responses. This attenuated BRS profile was coupled with dominant α-adrenergic response patterns, which was associated with an elevation of ambulatory blood pressure. BRS attenuation (rest and stress response) was not associated with left ventricular hypertrophy. It was concluded that lower BRS, especially during stress, may pose a significant health threat
viii
for urban African men regarding the development or promotion of α-adrenergic-driven hypertension and higher cardiovascular disease risk.
The aim of the second sub-study (Chapter 3) was to investigate possible associations between structural vascular disease (carotid intima-media thickness as marker), autonomic function (MHPG as marker) and nocturnal blood pressure in the African and Caucasian men. Results showed a higher prevalence of nocturnal hypertension in the African men, with night-time blood pressure significantly higher compared to the Caucasian men. In the African and Caucasian men, carotid intima-media thickness was linearly predicted by nocturnal systolic and diastolic blood pressure respectively. In conclusion, no associations were demonstrated between MHPG and carotid intima-media thickness or between MHPG and nocturnal blood pressure. Elevated nocturnal blood pressure evidently seems to promote structural vascular disease in this cohort of urban African and Caucasian men.
The aim of the third manuscript presented in Chapter 4, was to investigate bio-availability of NO during mental challenge (autonomic function marker) and the possible association with structural vascular disease (carotid intima-media thickness as marker). In the African men, an attenuated NOx response was demonstrated to the Stroop colour-word conflict test. After stratification into high and low NOx response groups, in the African men with a low NOx response enhanced α-adrenergic with significant ST-segment depression responses was demonstrated indicating reduced myocardial oxygen supply during mental stressor exposure. Only in the African men, a ST-segment depression was significantly associated with structural vascular disease. It was concluded that the African men demonstrated a vulnerable cardiovascular profile. In this cohort of African men, the significant association between structural vascular disease and myocardial ischemia may particularly indicate a possible higher risk for future cardiovascular events.
ix General conclusion
Through the assessment of autonomic and cardiovascular responses a possible higher cardiovascular risk was demonstrated in the African men. In this cohort sympathetic hyperactivity was evident, coupled with dominant vascular response patterns and reduced myocardial oxygen supply during mental stress exposure. Based on these findings, this population group’s risk for accelerated target organ damage, as well as for future cardiovascular events, appear significantly higher than those of the Caucasian male cohort.
Keywords: Autonomic responses, cardiovascular function, hypertension, target organ damage.
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AFRIKAANSE TITEL: Vergelyking van outonome en kardiovaskulêre response in Afrikane en Kaukasiër-mans: Die SABPA-Studie
OPSOMMING
Motivering
Hipertensie is ʼn pertinente gesondheidsprobleem vir verstedelikte swart Afrikaan mans (voortaan hierna verwys as Afrikane – met inbegrip van mans). Beide simpatiese hiperaktiwiteit en ʼn dominante α-adrenerge responspatroon is al geïmpliseer as bydraende faktore tot hulle swak kardiovaskulêre gesondheid. Benewens die nadelige effek van neurogeniese hipertensie op teikenorgane, bevorder simpatiese hiperaktiwiteit die versnelde ontwikkeling van linkerventrikulêre hipertrofie, strukturele vaskulêre siekte sowel as koronêre arteriële siekte.
Doelstelling
Die oorkoepelende doelstelling van hierdie studie was die bestudering van outonome beheer van die kardiovaskulêre sisteem in ʼn kohort van verstedelikte Afrikane en Kaukasiër mans tydens ʼn mentale uitdaging. Assosiasies is ondersoek tussen die potensiële simpato-vagale wanbalans, bloeddruk en teikenorgaan skademerkers om die moontlikheid van kardiovaskulêre risiko in die manlike etniese groepe vas te stel.
Metodologie
Die SABPA- (simpatiese aktiwiteit en ambulatoriese bloeddruk in Afrikane) studie het 200 manlike onderwysers (99 Afrikane en 101 Kaukasiër-mans) in die Kenneth Kaunda Onderwys-distrik van die Noordwes Provinsie, Suid-Afrika, as deelnemers betrek. Van die deelnemer-groep is HIV-geïnfekteerdes (13 Afrikane) en klinies bevestigde diabete (1 Kaukasiër en 6 Afrikane mans) uitgesluit van verdere analises. Stratifisering is gebaseer op
xi
etnisiteit en verder soos aangedui deur statistiese-interaksie-effekte. Kardiovaskulêre en outonome response is geëvalueer vir rus sowel as stressor-blootstelling (kouepressor-toets en Stroop kleur-woord konfliktoets). Outonome metings het baroreseptorsensitiwiteit (BRS), 3-metoksie-4-hidroksie-fenielglikol (MHPG) en nitro-oksiedmetaboliet- (NOx) vlakke ingesluit. Kardiovaskulêre veranderlikes het bestaan uit bloeddruk, kardiale omset, slagvolume, totale perifere weerstand, harttempo, arteriële meegewendheid en die ST-segment van die elektrokardiogram. Merkers van teikenorgaanskade het die Cornell-produk (aanduiding van linkerventrikulêre hipertrofie) en karotiese intimamedia-dikte as aanduiding van strukturele vaskulêre siekte ingesluit. Gemiddelde en proporsies is deur standaard
t-toetse en Chi-kwadraattoetse onderskeidelik vergelyk. Betekenisvolle verskille in
gemiddeldes van kardiovaskulêre en outonome metings is deur kovariansie-analises bepaal. Enkel- en multiveranderlike regressie-analises is aangewend om assosiasies te demonstreer tussen teikenorgaanskade en kardiovaskulêre en outonome merkers.
Resultate en gevolgtrekkings van onderskeie manuskripte
Om die outonome senuweestelsel en kardiovaskulêre funksie sowel as teikenorgaanskade te assesseer het ons duidelik gefokus op response waar ons deelnemers uitgedaag is. Merkers van outonome response wat geassesseer is, is BRS, 3-metoksie-4-hidroksie-fenielglikol en nitro-oksied metaboliete.
Die eerste manuskrip (Hoofstuk 2) het gefokus of linkerventrikulêre hipertrofie as merker van teikenorgaanskade, bloeddruk en BRS as merker van outonome funksie. Die doel was om vas te stel of baroreseptorsensitiwiteit betekenisvol laer in die Afrikane was as in die Kaukasiër mans. Verder is die moontlike assosiasie tussen verlaging van baroreseptorsensitiwiteit en verhoogde vlakke van ambulatoriese bloeddruk sowel as linkerventrikulêre hipertrofie in hierdie populasiegroepe ondersoek. Resultate het aangetoon dat die Afrikane betekenisvol laer baroreseptorsensitiwiteit stresresponse getoon het. Hierdie verlaagde baroreseptorsensitiwiteitsprofiel was gekoppel aan dominante α-adrenerge responspatrone wat geassosieer was met verhoging van
xii
ambulatoriese BP. Baroreseptorsensitiwiteitsverlaging (rustend en stresresponse) was nie geassosieer met linkerventrikulêre hipertrofie nie. Daar is tot die gevolgtrekking gekom dat laer baroreseptorsensitiwiteit, veral tydens stres ʼn betekenisvolle gesondheidsrisiko vir verstedelikte Afrikane inhou rakende die ontwikkeling of bevordering van α-adrenerggedrewe hipertensie en hoër kardiovaskulêre risiko.
Die doel van die tweede substudie (Hoofstuk 3) was om moontlike assosiasies te ondersoek tussen die strukturele vaskulêre siekte, outonome funksie (MHPG as merker) en nagtelike bloeddruk in die Afrikane en Kaukasiër mans. Resultate het aangedui dat daar ʼn hoër voorkoms van nagtelike hipertensie in die Afrikane voorkom, met nagtelike bloeddruk betekenisvol hoër as by die Kaukasiër mans. In die Afrikane en Kaukasiër mans was karotiese intimamedia-dikte liniêr deur nagtelike sistoliese en diastoliese bloeddruk onderskeidelik voorspel. Die gevolgtrekking was dat geen assosiasies bewys is tussen MHPG en karotiese intimamedia-dikte of tussen MHPG en nagtelike bloeddruk nie. Verhoogde nagtelike bloeddruk bevorder klaarblyklik strukturele vaskulêre siekte in hierdie kohort van verstedelikte Afrikane en Kaukasiër-mans.
Die doel van die derde manuskrip aangebied in Hoofstuk 4 was om die biobeskikbaarheid van NO tydens mentale uitdaging (outonomefunksie-merker) te ondersoek asook moontlike assosiasies met strukturele vaskulêre siekte (karotiese intima-media dikte as merker). By die Afrikane is verlaagde NOx response getoon met die Stroop kleur-woord konfliktoets. Na stratifisering in hoë en lae NOx responsgroepe, is daar in die Afrikane saam met die lae NOx respons ʼn verhoogde α-adrenerge respons met betekenisvolle ST-segment depressie getoon wat dui op verlaagde miokardiale suurstofvoorsiening tydens mentale stressor-blootstelling. Slegs in die Afrikane mans was die ST-segment depressie betekenisvol geassosieer met strukturele vaskulêre siekte. Daar is tot die gevolgtrekking gekom dat die Afrikane mans ʼn kwesbare kardiovaskulêre profiel toon. In hierdie kohort van Afrikane mans kan die betekenisvolle assosiasie tussen strukturele vaskulêre siekte en miokardiale ischemie veral dui op ʼn moontlike hoër risiko vir toekomstige kardiovaskulêre gebeurtenisse.
xiii Algemene gevolgtrekking
Deur die evaluering van outonome en kardiovaskulêre response in ʼn kohort van Afrikane en Kaukasiër mans, is ʼn betekenisvolle hoër kardiovaskulêre risiko aangedui vir die Afrikane mans. In hierdie kohort was simpatiese hiperaktiwiteit duidelik, gekoppel aan dominante vaskulêre responspatrone en verlaagde miokardiale suurstofvoorsiening tydens mentale stressor-blootstelling. Gebaseer op hierdie bevindinge is hierdie populasiegroep se risiko vir versnelde teikenorgaanskade sowel as vir toekomstige kardiovaskulêre gebeurtenisse oënskynlik betekenisvol hoër as dié van die Kaukasiër manlike kohort.
Sleutelwoorde: Outonome respons, kardiovaskulêre funksie, hipertensie, teikenorgaan-skade.
xiv
PREFACE
This thesis is presented in the article-format, consisting of peer-reviewed published or submitted articles. This format is approved, supported and defined by the North-West University guidelines for postgraduate PhD level studies. The first chapter of this thesis is a detailed literature overview, aside from the appropriate literature backgrounds discussed in each of the manuscripts. Chapters 2, 3 and 4 comprise the respective manuscripts in the form of original research articles. All articles were submitted for publication in peer reviewed journals. The promoter, co-promoter and assistant promoters were included as co-authors in each paper. The first author was responsible for initiation and all parts of this thesis, including literature searches, data mining and statistical analyses, the interpretation of results and writing of the research papers. All co-authors gave their consent that the research articles may form part of this thesis. References included in this thesis are according to the Vancouver format.
The first article was submitted to Blood Pressure journal (published), the second to Heart,
Lung and Circulation (in rebuttal) and the third to Journal of Hypertension (submitted).
Relevant references are given at the end of each chapter according to author’s instructions of each specific journal where papers were submitted.
xv
STATEMENT BY THE AUTHORS
The contribution of each researcher in this study is provided in the following table:
Me AS Uys Responsible for proposal of study, literature searches, design and planning of research articles and thesis, statistical analyses, interpretation of results and writing of entire thesis.
Prof L Malan Promoter. Guidance, intellectual input. Supervised the initial planning of thesis and design, collection of data and writing of thesis. Project leader of the SABPA study.
Prof JM van Rooyen Co-promoter. Intellectual input, data collection and assessment of content of thesis.
Prof HS Steyn Assistant Promoter. Intellectual input and assessment of validity of statistical methods followed.
Prof Dr T Ziemssen Assistant Promoter. Intellectual input in writing of research papers. Dr M Reimann Assistant Promoter. Intellectual input in writing of thesis.
xvi
The following is a statement of all co-authors verifying their individual contribution and involvement in this study and granting permission that the relevant research articles may form part of this thesis:
I hereby declare that I approved the afore-mentioned manuscripts and that my role in this study, as stated above, is representative of my actual contribution and that I hereby give my consent that these manuscripts may be published as part of the PhD thesis of Aletta S Uys.
________________ ___________________ _______________
Prof L Malan Prof JM van Rooyen Prof HS Steyn
_________________ ________________ Dr M Reimann
xvii
LIST OF TABLES AND FIGURES
A. TABLES
CHAPTER 2:
TABLE 1 – Characteristics of participants as indicated through univariate analysis.
TABLE 2 – Independent associations of cardiovascular variables with ambulatory blood pressure in Africans and Caucasian men.
TABLE 3 – Independent associations of cardiovascular variables with the Cornell product in African and Caucasian men.
CHAPTER 3:
TABLE 1 – Characteristics of African and Caucasian male participants as indicated through descriptive statistics.
TABLE 2 – Adjusted results for African and Caucasian nocturnal hypertensive men.
TABLE 3 – Independent associations of cardiovascular variables measurements with carotid intima-media thickness (dependent variable) in African and Caucasian nocturnal hypertensive men.
CHAPTER 4:
TABLE 1 – Characteristics of the study group.
TABLE 2 – Comparison of C-reactive protein nitric oxide metabolite and cardiovascular measurements between African and Caucasian men.
TABLE 3 – Comparison of NOx and cardiovascular responses to the colour-word conflict test between African and Caucasian men.
TABLE 4 - Independent associations between far wall carotid intima-media thickness and cardiovascular measurements (dependent variable) in African and Caucasian low NOx response groups.
xviii B. FIGURES
CHAPTER 1:
FIGURE 1 – Innervation of sympathetic and parasympathetic nerves with the heart and blood vessels.
FIGURE 2 – Diagram illustrating the path from catecholamine synthesis to elimination. FIGURE 3 – A proposed model of stress reactivity and cardiovascular disease.
FIGURE 4 – Hypothesized influence of a sympatho-vagal imbalance and dominant vascular (α-adrenergic) response pattern on the cardiovascular profile in a cohort of African men.
CHAPTER 2:
FIGURE 1 – A comparison of resting cardiovascular and left ventricular hypertrophy variables between African and Caucasian men.
FIGURE 2 – A comparison of the aggregated cardiovascular stress responses between African and Caucasian men.
CHAPTER 3:
FIGURE 1 – Associations between nocturnal heart rate and MHPG in African and Caucasian men.
FIGURE 2 – Adjusted for age, body surface area, physical activity, cotinine, γ-GT, cholesterol and CRP.
CHAPTER 4:
FIGURE 1 – A comparison of cardiovascular responses between high and low NO response groups of the African (A) and Caucasian (B) men.
FIGURE 2 – Associations with CIMT (mm) using stepwise multiple linear regression in African and Caucasian men.
xix
LIST OF ABBREVIATIONS
α – Alpha
β – Beta
Δ – Relative change
μmol/l – Micromole per litre
γ-GT – Gamma-glutamyl transferase ABPM – Ambulatory blood pressure ADH – Alcohol dehydrogenase
AIDS – Acquired Immune Deficiency Syndrome AMS – Artery measurement system
ANCOVA – Analysis of covariance ATP – Adenosine triphosphate
BMI – Body mass index
BP – Blood pressure
bpm – Beats per minute BRS – Baroreceptor sensitivity BSA – Body surface area
°C – Degrees Celsius
cAMP – cyclic adenosine monophosphate CW – Windkessel arterial compliance CIMT – Carotid intima-media thickness
CIMTf – Carotid intima-media thickness of the far wall
cm – Centimetre
CO – Cardiac output
COMT – Catechol-O-methyltransferase CRP – C-reactive protein
xx DBP – Diastolic blood pressure DHPG – 3,4-dihydroxy-phenylglycol ECG – Electrocardiogram
ECLA – Electrochemiluminescence immunoassay ESH – European Society of Hypertension
Et al. – Et alia “and others”
FMS – Finapres Medical Systems
h – Hours
HIV – Human immunodeficiency virus kcal – Kilocalories
kg – Kilogram
kg/m2 – Kilograms per meter squared
HPLC – High performance liquid chromatography
ISAK – International society for the advancement of kinanthropometry L/min – Litre per minute
LVH – Left ventricular hypertrophy m2 – Square metre
MAO – Monoamine oxidase
MD – Medical doctor
MHPG – 3-methoxy-4-hydroxy-phenylglycol MHz – Mega Hertz
min – Minute
mg/L – Milligrams per litre
ml/mmHg – Millilitre per millimetre Mercury
mm – Millimetre
mmHg – Millimetre Mercury
mmHg/ml/s – Millimetre Mercury per millilitre per second mmol/L – Millimole per Litre
xxi
MN – Metanephrines
ms/mmHg – Milliseconds per millimetre Mercury
mV – Millivolt
mV.ms – Millivolt by millisecond
n – Number of
ng/ml – Nanogram per millilitre NMN – Normetanephrines
NO – Nitric oxide
NOx – Nitric oxide metabolite NWU – North-West University
p – Probability
pmol/l – Picomole per litre r – Correlation coefficient
R2 – Relative predictive power of a model
RN – Registered nurse
SABPA – Sympathetic activity and Ambulatory Blood Pressure in Africans SBP – Systolic blood pressure
SD – Standard deviation
SE – Standard error
SMAC – Sequential Multiple Analyser Computer
SV – Stroke volume
TPR – Total peripheral resistance U/l – Units per litre
USA – United States of America VMA – Vanillylmandelic acid
1
CHAPTER 1
2
1. INTRODUCTION
Over 200 years ago, it was postulated that the muscle fibres of blood vessel walls may be under neural control.1 Since then, research has shown that the heart as well as smooth muscle of the vascular walls are richly innervated with nerve fibres of the autonomic nervous system.1
The autonomic nervous system consists of two major pathways, the sympathetic and parasympathetic nervous system.2,3 The reciprocal functioning of these two pathways allows the maintenance of homeostatic conditions, by continuously responding to internal and external stimuli (e.g. exercise, stressor exposure and orthostatic changes).4,5 A concept, namely the sympatho-vagal balance, is often referred to when one system is activated and the other is inhibited.6 Regarding the cardiovascular system, increased sympathetic stimulation and subsequent increase in catecholamine secretion leads to elevation in heart rate and contractile force as well as an increase in blood pressure.7 Parasympathetic stimulation results in a slower heart beat and a decrease in blood pressure.7 Activity of sympathetic and parasympathetic activity regarding cardiovascular control must be kept in check by a reflex arch known as the baroreceptor reflex.8 This reflex arch appropriately adapts autonomic activity in response to cardiovascular changes.8
The autonomic nervous system not only plays a vital role in regulating instantaneous cardiovascular responses to stimuli,6,9 it also regulates the circadian pattern the cardiovascular system follows.8 During the day, the sympathetic nervous system dominates and appropriately responds to everyday stimuli (fight-or-flight response) by adapting catecholamine secretion appropriately. At night during sleep the dominating influence of the parasympathetic nervous system sets the body in its “rest and digest” mode by decreasing heart rate and blood pressure to much lower levels compared to that of daytime.10
3
Although this regulatory interaction may sound simple, it is far from it. The autonomic nervous system’s involvement in cardiovascular control entails a complex and dynamic relationship of various messengers, receptors and effector cells.11 This relationship varies from appropriate cardiovascular control by the baroreceptor reflex arch,12 catecholamine secretion9 as well as bio-availability of the powerful vasodilator, nitric oxide.13 In the event of dysfunction of any of these components, pathological cardiovascular changes are promoted.1 This literature review will focus on various aspects of autonomic control of the cardiovascular system (baroreceptor sensitivity, catecholamine secretion and nitric oxide bio-availability). The pathology associated with cardiovascular autonomic dysregulation will particularly be assessed and what this may entail for urban African men.
2. AN OVERVIEW OF AUTONOMIC CONTROL OF CARDIOVASCULAR
FUNCTION
2.1. Central nervous system control
Although the autonomic nervous system is responsible for cardiovascular control, its activity is regulated by other sections of the central nervous system including the medulla oblongata, hypothalamus and cortical regions.14 Located within the medulla are the cell bodies of both sympathetic and parasympathetic afferent nerves. The hypothalamus is responsible for integration and coordination of medullary activity and higher cortical regions are responsible for adapting autonomic control associated with emotion or fear, e.g. blushing or increased heart rate and other.14 Peripheral receptors located throughout the body send sensory information to specific regions of the brain and autonomic activity is adjusted to alter cardiovascular function accordingly.15
4
2.2. The sympathetic nervous system and its role in cardiovascular control
Neurons that are responsible for the sympathetic (or adrenergic) control of the cardiovascular system originate in the medulla oblongata, their axons (preganglionic fibres) progress down the spinal cord and exit between segments T-1 and L-2 (from the thoracic and lumbar regions).2,16 Some of the preganglionic sympathetic nerves enter paravertebral ganglia and travel within the ganglia to synapse with postganglionic fibres, which innervate with the heart and blood vessels. Other preganglionic sympathetic nerves, generally from the lower thoracic and upper lumbar regions, synapse in pre-vertebral ganglia and synapse with postganglionic fibres. These fibres primarily innervate the vasculature (Figure 1).15 Additionally, a collection of postganglionic sympathetic nerves never develop axons. Jointly, they form the endocrine glands called the adrenal medullae.3Within the terminal endings of the sympathetic nerves, norepinephrine, the main neurotransmitter, and epinephrine are synthesized and stored in vesicles (Figure 2).17 Epinephrine and norepinephrine are collectively called catecholamines. Upon adrenergic stimulation, the storage vesicles release their contents into the synaptic gap. Located on the external cell membrane of the effector cells (heart and blood vessels) are specific areas where the catecholamines bind, called adrenergic receptors. These receptors are divided into two subtypes, alpha (α) and beta (β) which in turn are divided into types one and two.2
In response to sympathetic stimulation, e.g. in the event of stress exposure, the adrenal medullae additionally releases epinephrine and norepinephrine into the circulation. The additive effect of the secreted catecholamines is relatively slower compared to the effect of direct sympathetic stimulation of the vasculature and the heart.3
5
Figure 1: Innervation of sympathetic and parasympathetic nerves of the heart and blood vessels.
Preganglionic fibres of the tenth cranial nerve (parasympathetic) represented by the solid red line (A), travel to the heart. Some of the preganglionic fibres that arise from thoracic and lumbar regions enter paravertebral ganglia to synapse above (B) or below entry level, others at their level of entry (C). The dotted black line represents the cervical ganglia which innervate the heart and the thoracic ganglia of which the latter innervate blood vessels as well as the heart. Preganglionic fibres originating from the upper lumbar and lower thoracic regions synapse with prevertebral ganglia (D), which travel to the vasculature. Excerpt from “Klabunde.2005”15
6
Figure 2: Diagram illustrating the path from catecholamine synthesis to elimination. The major
metabolic pathway is indicated by the thick blue line. Abbreviations: MAO, monoamine oxidase; DHPG, 3,4-dihydroxy-phynylglycol; COMT, catechol-O-methyltransferase; MN, metanephrines; NMN, normetanephrines; MHPG, 3-methoxy-4-hydroxy-phenylglycol; ADH, alcohol dehydrogenase; VMA, vanillylmandelic acid. Adapted from “Currie et al., 2012” and “Eisenhofer et al., 2004” 17,18
2.2.1. Adrenergic control of the heart
Located within the heart (myocardium as well as conduction system) are β1-adrenergic receptors.16 Stimulation of the receptors located in the Sino-atrial node increases activity of the enzyme adenylate cyclase, which stimulates the Gs-protein (stimulatory G protein). This protein in turn increases the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), increasing the rate of spontaneous pacemaking.9,15,19 As a result, the heart rate increases. Within the myocardium, cAMP increases the amount of open calcium channels, promoting the greater influx of calcium into the myocardial cells. The
7
release of calcium from the sarcoplasmic reticulum stores are increased as well. This results in a significant increase of the heart’s contractile force.20 Sympathetic stimulation therefore increases heart beats per minute as well as the force of each contraction.7
2.2.2. Adrenergic control of the vasculature
Sympathetic stimulation is the key role player of blood pressure regulation.8,21 There are two types of adrenergic receptors involved in the control of the diameter of arteries and arterioles.2 Stimulation of the α-adrenergic receptor type 1 results in vasoconstriction whilst stimulation of α-adrenergic receptor type 2 results in vasodilation. However, a predominantly vasoconstrictory effect is achieved by binding of norepinephrine to α1-adrenergic receptors on the vascular smooth muscle.8 Vasoconstriction is accomplished by activation of another G-protein (Gh-protein) which increases the activity of the enzyme, phospholipase C. This enzyme splits the compound phosphatidylinositol into IP3 (Inositol Triphosphate) and DAG (Diacylglycerol). IP3 increases the release of calcium from sarcoplasmic reticulum stores, resulting in contraction of vascular smooth muscle and reduction of vascular diameter.8 Pressure within the blood vessel increases as a result.
Opposing the vasoconstrictory effect of α-adrenergic stimulation is the vasodilatory effect of β2-adrenergic receptor stimulation.16 Binding of epinephrine and norepinephrine to this receptor increases the activity of the calcium pump of the sarcoplasmic reticulum, thereby enhancing the reuptake of calcium from cytoplasm.15 Interestingly, the overall effect of sympathetic stimulation of the vasculature results in vasoconstriction.8 It has been theorized that this is due to a possible larger density of α1-adrenergic receptors and that the receptors are located closer to the site of norepinephrine release.8
It should also be noted that sympathetic stimulation of the vasculature never ceases. Instead, due to continuous tonic sympathetic stimulation, blood vessels are continuously in a
8
partial state of constriction to maintain vascular tone, which varies depending on the rate of sympathetic stimulation.22
2.2.3. Catecholamine elimination
After being released, catecholamines are eliminated by various pathways. There are three routes of elimination, which entails diffusion into the circulation, destruction by tissue enzymes, and elimination through re-uptake by the adrenergic nerve endings.18 The latter is the main route of catecholamine metabolism.9 Neuronal and extra-neuronal metabolisation of catecholamines is depicted in Figure 2. Through the various routes of elimination, the major metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) is formed and converted mainly in the liver (by oxidation) to the end-product of epinephrine and norepinephrine metabolism, vanillylmandelic acid (VMA) which is excreted in the urine.18 MHPG is often measured experimentally in plasma and saliva as indication of sympathetic activity.23-25
2.2.4. Adrenergic stress response patterns
The sympathetic system enables the body to respond almost instantaneously during daily life to internal and external stimuli, often referred to as the “fight or flight” reaction.10 There are two major types of response patterns, α- or β-adrenergic, that may occur in the event of stress exposure or a mixture of the two. An α-adrenergic response pattern, which is characterised by increased total peripheral resistance, diastolic blood pressure as well as a decrease in arterial compliance.8 A dominant β-adrenergic response pattern entails an increase in systolic blood pressure, heart rate and cardiac output.8 Acute laboratory stress exposure has been used by researchers for years with the aim to mimic everyday life situations and observe the cardiovascular responses that are stimulated.26 Some stressors are used to evoke a dominant α-adrenergic response and others a dominant β-adrenergic response.27
9
A popular laboratory stressor used to evoke a dominant α-adrenergic response is the cold pressor test.27 This stressor entails the immersion of a hand or foot in icy water.28 It has been postulated that if individuals display an exaggerated vascular response to the cold pressor test, they are likely to develop hypertension.28 Another mental stress test often used, is the colour-word conflict test. Successive series of five colour words written in incongruent colours are shown in random order. The person exposed to this test is then required to recognize and verbally confirm the colour of a given word within a certain time limit.29 This laboratory stressor has been noted to elicit a mixed α-β adrenergic response.27
However, contradictory to the above-mentioned, an alternative theory has been developed. Kamarck et al. 29 and Lovallo et al.30 both noted that an individual is more likely to have a dominant adrenergic type response in general, rather than the response depending on the stressor. Therefore they are likely to have a “vascular” (α) or “cardiac” (β) response pattern, regardless of the stressor. However, it also depends on lifestyle factors. When urban dwelling Africans are exposed to stress, an α-adrenergic response pattern dominates.31 However, in Africans residing in a rural environment, stressor exposure rather elicits a central β-adrenergic response pattern.31 This shift of a central to a peripheral response pattern may be due to the adaptation of individuals, residing in an urban environment, to westernized habits. These habits include smoking, excessive alcohol use, unhealthy diets (processed foods, high salt intake) and lower physical activity.32,33
2.3. The parasympathetic nervous system and its role in cardiovascular control
Preganglionic parasympathetic nerve fibres (also referred to as cholinergic fibres) originate within the medulla oblongata. Their cell bodies are found in collective regions called dorsal vagal nucleus and nucleus ambiguous (collectively the cardio-inhibitory centre).15 Efferent fibres leave the medulla oblongata through cranial nerves III, IX and X and innervate the10
heart and vasculature.2,16,34 Within postganglionic cholinergic fibres, the neurotransmitter acetylcholine is synthesized and stored within vesicles.34 When stimulated, acetylcholine is released and binds to a specific site located on the cell membrane of the effector cell, called a muscarinic receptor.3,20
2.3.1. Cholinergic control of the heart
Upon cholinergic stimulation, acetylcholine is released from parasympathetic terminal nerve endings at specific sites of the heart.15 Occupation of sino-atrial node muscarinic receptors stimulates the αi component of the G-protein, opening the G-dependent potassium channels.35 Permeability for potassium is increased, promoting the outward flow of potassium which results in slower spontaneous action potential generation (pacemaking). Furthermore, binding of acetylcholine to muscarinic receptors of myocytes stimulates the inhibitory G-protein, decreasing the activity of the enzyme adenylate cyclase. The formation of cAMP is hampered, reducing the entry of calcium into cytoplasm and thus the contractile force of the heart.8,14
2.3.2. Cholinergic control of the vasculature
The direct vascular innervation by parasympathetic nerves is to a much lesser extent than sympathetic innervation.12 In the vasculature receiving parasympathetic stimulation, e.g. the coronary circulation,36 acetylcholine binds to muscarinic receptors located on the vascular endothelium, stimulating the release of the vasodilating agent, nitric oxide (NO).8 Nitric oxide is synthesized from the semi-essential amino acid, L-arginine.37 This process is catalized by the enzyme, nitric oxide synthase (NOS), which has three isoforms. The isoforms include endothelial NOS (eNOS), neuronal NOS (nNOS) and immunological NOS (iNOS).37 In the vascular smooth muscle, NO stimulates the enzyme guanylate cyclase, in turn increasing the formation of vasodilatory cyclic guanosine monophosphate.8
11 2.3.3. Elimination of acetylcholine
After its release into the synaptic space, acetylcholine will continue to stimulate the cholinergic receptors until it is metabolised. This is achieved by the enzyme, acetylcholinesterase, splitting acetylcholine into its metabolites choline and acetate.10 Choline is reabsorbed by the presynaptic terminal, where it is used to synthesize asetylcholine.3
2.4. Regulating adrenergic and cholinergic control of cardiovascular function –
the baroreceptor reflex
Arterial pressure is continuously monitored by a powerful central operating system.38 This negative feedback system, known as the baroreceptor reflex, prevents blood pressure from increasing too high or decreasing too low, by promptly adjusting the autonomic stimulation of the cardiovascular system.38 The sensitivity of the baroreceptor reflex system is often used to evaluate the efficacy of autonomic control of the cardiovascular system.12
Baroreceptors are mainly found in the aorta and carotid arteries, with major density in the aortic arch and carotid bifurcations.2 These mechanoreceptors respond to stretching of the arterial walls. In the event of arterial pressure elevation, the receptors respond by increasing their rate of action potential generation.7 The largest increase in firing rate of baroreceptors occurs at a specific mean arterial pressure value at about 100 mmHg, known as the set point.39
Action potentials generated in baroreceptors, which are located in the carotid bifurcation, travel along the carotid sinus nerve, joining the glossopharyngeal nerves before entering the medulla oblangata. From aortic baroreceptors, afferent fibres travel along the vagus nerves travelling to the medulla oblangata.14 Signals are particularly conveyed to the nucleus tractus
12
solitarius and relayed to higher brain structures. This includes the hypothalamus, where integration of signals takes place.40 The blood vessels and heart therefore are the effectors of the reflex arch. In response to an increased rate of signals received from the baroreceptors, tonic sympathetic stimulation of the cardiovascular system is inhibited whilst activity of cardiac parasympathetic nerves is augmented.14 Reflex bradycardia (reduced heart rate) as well as a reduction in heart contractile force, total peripheral resistance and venous return occurs as a result. These changes collectively result in blood pressure reduction.12
In the event of a decrease in blood pressure, the rate of signals received by the medulla oblangata from the baroreceptors lessens. In response, the medulla oblangata induces increased adrenergic stimulation and subsequently an attenuation of vagal stimulation of the cardiovascular system.15 The result is an increase in heart rate (tachycardia), increased contractile force as well as elevation of total peripheral resistance and venous return, all contributing to an increase of arterial pressure.12
2.5.
Relationship between autonomic cardiovascular control and the
endothelium
The autonomic control of cardiovascular responses cannot be studied without taking into account the important role of the endothelium.13 The endothelium, a single cellular layer forming the inner lining of blood vessels maintains the balance between the effects of sympathetic and parasympathetic stimulation of the vasculature.13 During rest, continuous blood flow through the vascular system causes friction against blood vessel lining, which is called shear stress.20 This friction stimulates the endothelium to release NO which counteracts the vasoconstrictive effect of tonic sympathetic stimulation.41 In the event of increased sympathetic stimulation, an augmentation of shear stress occurs as a result of vasoconstriction and subsequent increase in blood flow.42 This stimulates greater endothelial
13
release of NO, promoting vasodilation by inhibiting central and peripheral sympathetic activity.43
Located on endothelial cells are α2- as well as β2-adrenergic receptors. Sympathetic stimulation of α2-receptors results in endothelial release of NO, thereby counteracting the vasoconstrictive effect of vascular smooth muscle α1-adrenergic receptor stimulation.44 The function of endothelial β-adrenergic receptors is still quite unclear, although it has been postulated that they also have a role in promoting vasodilation through NO release.44 It is important to note that the endothelial layer must be intact for it to elicit a vasodilatory effect through NO release.50 In the event of endothelial damage, NO bio-availability is reduced significantly. Vasoconstriction is particularly promoted, decreasing vascular diameter and resulting in reduced blood supply to the specific affected area.13
3. AUTONOMIC AND CARDIOVASCULAR DYSFUNCTION
3.1. The neurogenic component of hypertension
The focus to this point has been on how the autonomic nervous system achieves its goal in controlling cardiovascular function to meet the demands of everyday life. With the ever increasing prevalence of cardiovascular disease, the possible contribution of autonomic cardiovascular dysregulation cannot be ignored. It comes as no surprise that indeed, a significant association was established between cardiovascular disease, particularly hypertension and sympatho-vagal imbalance.46 This imbalance is characterised by sympathetic hyperactivity (demonstrated through elevated norepinephrine spill-over and increased rate of sympathetic nerve firing) as well as decreased parasympathetic activity.47-50
14
To date it is still unclear what initially causes the sympatho-vagal imbalance.7 Growing evidence indicates chronic exposure to psychosocial stress as a possible culprit.51 However, not only the exposure, but also the response elicited need to be taken into account. Exaggerated cardiovascular responses have significantly been linked to the development of hypertension.31,52 Light et al.53 demonstrated that exaggerated cardiovascular reactivity particularly promoted by high levels of stress exposure during everyday life predicted elevation of blood pressure over 10 years.
By observing an individual’s response pattern to an acute, controlled physical or mental stressor, an indication may be given of the complex physiological mechanisms involved in cardiovascular disease development.54,55 As previously mentioned, certain individuals are prone to have a vascular (α) type response whilst others exhibit a predominant cardiac (β) response pattern.25,49 In hypertensive individuals, an exaggerated vascular response, coupled with reduced β-adrenergic response, has proven to promote chronic blood pressure elevation.56,57
3.1.1. Reduced baroreceptor sensitivity
Another underlying neurogenic mechanism for hypertension development is the reduction of baroreceptor sensitivity (BRS).21 The question may be raised as to why? The answer is multifaceted. The emphasis, however, falls on the attenuation of BRS as manifestation of sympathetic hyperactivity as well as reduced parasympathetic control.11,58,59
In an attempt to continuously compensate for exaggerated vascular responses, the baroreceptors are overstimulated, resulting in desensitization.2 With frequently occurring episodes of blood pressure elevation coupled with exaggerated cardiovascular responses,
15
hypertension development is accelerated.60 It has also been indicated that if blood pressure levels remain elevated for a prolonged period, the firing rate of the baroreceptors decrease gradually. Eventually it reaches the initial set point firing rate,14,61 hereby contributing to maintaining higher blood pressure.11 If blood pressure levels remain high, subsequent remodelling of arterial walls and increase in stiffness occurs. This further impairs the baroreceptors’ ability to stretch and therefore their ability to respond to elevation of blood pressure.11,62 Sympathetic tone is sustained and parasympathetic inhibition impaired, markedly contributing to a hypertensive state.63
3.1.2. Nocturnal hypertension
Autonomic dysregulation of cardiovascular function is not only apparent during stress but also impairs the circadian rhythm of cardiovascular function.64 This impairment is characterised by a shift from parasympathetic to sympathetic predominance during sleep,65 promoting nocturnal blood pressure and heart rate elevation.66 According to the European Society of Hypertension, nocturnal hypertension is defined as systolic and/or diastolic blood pressure above120 mmHg and 75 mmHg respectively.67
Abnormal nocturnal blood pressure is regarded as a significant risk factor for cardiovascular morbidity and mortality68 by promoting target organ damage and future cardiovascular events.69,70 Sympathetic hyperactivity in itself promotes structural vascular disease by increasing inflammatory responses as well as growth factor secretion. This eventually leads to vascular wall thickening and formation of atherosclerotic plaques.13
16
3.2. Target organ damage development
3.2.1. Atherosclerosis
Atherosclerosis is often referred to as a neurogenic phenomenon,51 with sympathetic hyperactivity particularly contributing to the promotion of cardiovascular disease.71 Sympathetic hyperactivity has a significantly detrimental influence on the endothelium.13 With exaggerated stress-induced blood pressure responses resulting in excessive shear stress, the endothelial layer is eventually damaged72-74 resulting in impaired NO release and eventually vasoconstriction.75
Endothelial dysfunction is considered one of the most pertinent contributing factors of atherogenesis.75 Endothelial nitric oxide normally inhibits atherosclerotic processes by reducing leukocyte adhesion and platelet aggregation.76 In the event of endothelial damage, disrupted NO bioavailability leads to increased adhesion and migration of leukocytes into vascular wall promoting inflammation, lipid incorporation and vascular disease development is promoted.77,78 Growth factors are also released which stimulate smooth muscle cell proliferation and subsequently an increase in vascular wall thickness, inevitably resulting in full blown atherosclerosis.78,79
Endothelial dysfunction of the coronary circulation80 leads to impaired coronary vasodilation in response to shear stress.45 During sympathetic stimulation brought about by daily life occurrences, e.g. mental stress and exercise vasoconstriction is exaggerated at sites where the endothelium is damaged (Figure 3).74 When cardiac work increases (as during physical activity) impaired vasodilation and exaggerated vasoconstriction elicits myocardial ischemia.81,82 This is particularly indicated by an ST-segment depression on Holter ECG.54,83 These plethora of events manifest inevitably as coronary artery disease84 increasing the risk markedly for future cardiovascular events.83
17 3.2.2. Left ventricular hypertrophy
A growing body of evidence has indicated that sympathetic hyperactivity contributes to acceleration of left ventricular hypertrophy development.85 Greenwood et al. 86 demonstrated the presence of greater sympathetic outflow results in an accelerated development of left ventricular hypertrophy in patients with hypertension. The sympathetically mediated increase in peripheral resistance and resultant arterial stiffening, leads to pulse wave augmentation which in turn increases cardiac afterload.87 Thus, for a specific stroke volume, a higher more myocardial force is required to eject blood into the aorta. Over time cardiac myocytes undergo hypertrophic changes and become unable to relax. Diastolic dysfunction commences.88
Regardless of the additive effects of sympathetic hyperactivity to hypertension, adrenergic overdrive independently contributes to left ventricular hypertrophy.86 Studies in animal models89,90 and in humans have shown increased norepinephrine levels induce an increase of cardiac myocyte size (Figure 3).86,91 The relationship between sympatho-vagal dysregulation and both left ventricular hypertrophy as well as diastolic dysfunction has particularly been demonstrated by reduced BRS.92,93
18
Figure 3: A proposed model of stress reactivity and cardiovascular disease. The mechanisms leading to pre-clinical risk may not act independently of one another, but to some extent be caused or influenced by each other. Abbreviations; ET, endothelial; RAAS, the renin-angiotensin-aldosterone system; IRS, insulin resistance;CVD, cardiovascular disease Excerpt from“Hamer & Malan, 2010”32
19
4. AUTONOMIC AND CARDIOVASCULAR DYSFUNCTION CONCERNING
AFRICANS
The prevalence of developing cardiovascular diseases is ever growing globally.94 It is predicted that by 2030 ischemic heart disease and stroke will be the major cause of mortality worldwide.95 In sub-Saharan Africa the incidence of cardiovascular disease has been predicted to double by 2020.96 A significantly higher prevalence of hypertension has been documented by the NHANES study in African Americans when compared to their Caucasian counterparts.97 In this population group, especially men, research has implicated a high exposure to psychosocial stress98 in turn resulting in sympathetic hyperactivity with an exaggerated vascular resistance response pattern.99
Regarding South Africa, hypertension in particular has also been indicated as a significant health issue for the urban dwelling black African community, especially men. 100-102 The same pattern has been implicated in cardiovascular disease development as is the case with African Americans. Sympathetic hyperactivity’s involvement as possible contributing factor has also been postulated in this population group.31,103,104 Studies have also indicated that Africans have a propensity of a dominant vascular response pattern when exposed to stressors,31,54,104,105 increasing this population group’s risk for cardiovascular disease.100
An additional alarming observation is that black population groups tend to have a high prevalence of nocturnal hypertension.106 This may also be the case for urban Africans, based on the suggested sympatho-vagal imbalance,66 rendering them even more vulnerable to target organ damage85 and future cardiovascular events.68
20
The suggested sympatho-vagal imbalance in Africans, especially urban African men, paints a grim picture for their cardiovascular health. A limited number of studies have, however, attempted to assess different components of autonomic control of the cardiovascular system and related responses. It is particularly important to establish whether this suggested pattern of dysregulation does exist in this population group.
5. AIMS
5.1. Overarching aim
The main aim of this thesis was to examine and compare a cohort of African and Caucasian men regarding different aspects of autonomic control of the cardiovascular system including resting and mental stress responses. When the proposed presence of a sympatho-vagal imbalance is established in one of or both the groups, possible associations with bio-availability of NO, blood pressure elevation and target organ damage markers will be examined to determine possible cardiovascular risk.
5.2. Detailed aims
5.2.1. Chapter 2 – Baroreceptor sensitivity, cardiovascular responses and ECG left ventricular hypertrophy in men: The SABPA study
The aims of this research article were:
To determine whether BRS is significantly lower in a cohort of urban African men than in their Caucasian counterparts.
To determine whether attenuated BRS (during rest and stressor exposure) is significantly associated with blood pressure elevation as well as left ventricular hypertrophy in these population groups.
21
5.2.2. Chapter 3 – Nocturnal blood pressure, 3-methoxy-4-hydroxy-phenylglycol and carotid intima-media thickness: The SABPA study
The aim of this research article was:
To assess differences between urban African and Caucasian men in terms of
o Sympathetic activity with salivary 3-methoxy-4-hydroxy-phenylglycol as marker of sympathetic activity (resting responses were observed only as correlations were observed with nocturnal blood pressure, therefore a resting state).
o Nocturnal blood pressure.
o Structural vascular disease with carotid intima-media thickness as marker.
5.2.3. Chapter 4 – Nitric oxide, cardiovascular function and structural vascular disease in men: The SABPA study
The aim of this research article was:
To explore the relationship between NO metabolite responses resting as well as to a mental stressor, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men.
6.
HYPOTHESES
6.1. Overarching hypothesis
The overarching hypothesis of this thesis was that the cohort of urban African men will demonstrate a disrupted sympatho-vagal balance, characterized by sympathetic hyperactivity and/or attenuated parasympathetic activity. This imbalance will be coupled by a dominant vascular resting and stressor response pattern, in other words a dominant
22
α-adrenergic response pattern). The above-mentioned will be associated with a deleterious cardiovascular profile and markers of target organ damage (Figure 4).
6.2. Detailed hypotheses
6.2.1. Chapter 2 – Baroreceptor sensitivity (BRS), cardiovascular responses and ECG left ventricular hypertrophy in men: The SABPA study
In this article it was hypothesized that:
African men will have significantly lower BRS (during rest and stressor exposure) than the Caucasian men.
In the African men, attenuated BRS will be associated with ambulatory blood pressure.
In the African men, attenuated BRS will be associated with ECG left ventricular hypertrophy.
6.2.2. Chapter 3 – Nocturnal blood pressure, 3-methoxy-4-hydroxy-phenylglycol (MHPG) and carotid intima-media thickness: The SABPA study
In this article it was hypothesized that:
The African men will display significantly higher nocturnal blood pressure values than the Caucasian men.
MHPG will be significantly higher in the African men compared to their Caucasian counterparts.
MHPG and nocturnal blood pressure will be associated with structural vascular disease in nocturnal hypertensive African men.
23
6.2.3. Chapter 4 – Nitric oxide, cardiovascular function and structural vascular disease in men: The SABPA study
In this article it was hypothesized that:
African men will have attenuated NO metabolite resting and stressor responses compared to the Caucasian men.
Attenuated NO responses will be associated with a detrimental cardiovascular profile and structural vascular disease in African men.
Figure 4: Hypothesized influence of a sympatho-vagal imbalance and dominant vascular (α-adrenergic) response pattern on the cardiovascular profile in a cohort of African men. Symbols: ↑, increase; ↓, decrease; α, alpha. Abbreviations: BRS, baroreceptor sensitivity; NO, nitric oxide.
24
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